SV40-dependent AKT activity drives mesothelial cell transformation after asbestos exposure

Our plain-English summary of SV40-dependent AKT activity drives mesothelial cell transformation after asbestos exposure, by P. Cacciotti, D. Barbone, C. Porta, et al (Cancer Research, 2005).

The study

• Authors: P. Cacciotti, D. Barbone, C. Porta, D.A. Altomare, J.R. Testa, L. Mutti, G. Gaudino
• Journal: Cancer Research
• Published: 2005;65(12):5256-62
• Cited by: 71 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Human malignant mesothelioma is an aggressive cancer generally associated with exposure to asbestos, although SV40 virus has been involved as a possible cofactor by a number of studies. Asbestos fibers induce cytotoxicity in human mesothelial cells (HMC), although cell survival activated by key signaling pathways may promote transformation. We and others previously reported that SV40 large T antigen induces autocrine loops in HMC and malignant mesothelioma cells, leading to activation of growth factor receptors. Now we show that SV40 induces cell survival via Akt activation in malignant mesothelioma and HMC cells exposed to asbestos. Consequently, prolonged exposure to asbestos fibers progressively induces transformation of SV40-positive HMC. As a model of SV40/asbestos cocarcinogenesis, we propose that malignant mesothelioma originates from a subpopulation of transformed stem cells and that Akt signaling is a novel therapeutic target to overcome malignant mesothelioma resistance to conventional therapies.

In plain English

In this laboratory study, the authors exposed three primary human mesothelial cell cultures and two malignant mesothelioma cell lines to amosite and crocidolite asbestos, with glass fibers as a control. In the primary cells, both asbestos types were similarly toxic and more toxic than glass fibers. Mesothelial cells carrying the SV40 large T antigen, and the SV40-positive mesothelioma line, were more resistant to asbestos-induced cell death. This resistance depended on a signaling protein, Akt: blocking its pathway with the drug Wortmannin significantly increased cell death in these cells. Of 19 human mesothelioma tumors, 11 showed the SV40 antigen, and 10 of these also showed active Akt (P = 0.0408). Cells carrying the full SV40 genome were given two rounds of low-dose amosite and cultured for 60 days. They formed transformed cell clusters (foci) with active Akt. Cells carrying only the T antigen formed no foci; like unaltered mesothelial cells, they did not survive the full experiment. The authors concluded that prolonged low-dose amosite exposure induces transformation of these cells via Akt activation. They noted that transformation was shown only in the laboratory, and xenotransplant experiments would be needed to confirm it.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study of cultured human mesothelial cells and mesothelioma cell lines, some genetically altered to carry SV40 sequences, plus staining of human mesothelioma tumor samples on a tissue microarray
• Who was studied: Two malignant mesothelioma cell lines (MMB, SV40-negative; MMP, SV40-positive) derived from pleural effusions of mesothelioma patients. Three primary human mesothelial cell cultures from patients with congestive heart failure. A tissue microarray of 19 primary malignant mesothelioma tumor specimens from Fox Chase Cancer Center.
• Exposure: UICC amosite and crocidolite asbestos fibers, with glass fibers as control. Short-term doses went up to 10 micrograms per square centimetre for 24 hours. Long-term exposure was two 72-hour cycles of amosite at 2.5 micrograms per square centimetre, followed by culture for 60 days. Hydrogen peroxide and etoposide (VP-16) were also used as toxic agents.
• Main results:
  • In primary human mesothelial cells, amosite and crocidolite were similarly toxic, and both were significantly more toxic than glass fibers.
  • In human mesothelial cells, toxicity rose with dose for both fiber types. It started at the lowest concentration (1 microgram per square centimetre) and reached a plateau of about 50% at 10 micrograms per square centimetre.
  • Mesothelial cells carrying the SV40 large T antigen or SV40 DNA were intrinsically more resistant to asbestos toxicity, and so were the SV40-positive mesothelioma cells (MMP), whether or not the growth factor HGF was added. Normal mesothelial cells and SV40-negative MMB cells became significantly (P < 0.01) less sensitive only when stimulated with HGF.
  • Blocking the PI3K/Akt pathway with Wortmannin during asbestos exposure significantly (P < 0.001) increased toxicity in T antigen-expressing and HGF-treated cells. It did not do so in untreated mesothelial cells or SV40-negative MMB cells.
  • In the tumor tissue microarray, the SV40 large T antigen was found in 11 (58%) of 19 malignant mesothelioma tumors.
  • Active (phosphorylated) Akt was found in 10 of the 11 T antigen-positive tumors. T antigen positivity was associated with phospho-Akt positivity (P = 0.0408).
  • After 60 days of long-term amosite treatment, cells carrying the full SV40 genome lost contact inhibition and formed several foci. Cells carrying only the T antigen did not.
  • Control mesothelial cells and T antigen-only cells exposed to amosite did not survive the whole long-term experiment.
  • In cells derived from the foci, blocking Akt activity with 50 nmol/L Wortmannin significantly restored the toxic response.
• The authors' conclusion: The authors concluded that prolonged exposure to low doses of amosite fibers induces transformation of SV40-carrying human mesothelial cells through Akt activation. They proposed Akt signaling as a possible target for mesothelioma therapy.
• Limitations the authors state:
  • The authors stated that transformation was shown only in vitro and that xenotransplant experiments would be needed to validate the transformed phenotype.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: SV40, Mesothelial Cells, Asbestos Exposure, Malignant Mesothelioma, STEM.

Related studies

• Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth — D.A. Altomare, H. You, et al. (2005)
• beta1-integrin mediates asbestos-induced phosphorylation of AKT and ERK1/2 in a rat pleural mesothelial cell line — A. Berken, J. Abel, et al. (2003)
• Progressive aberrant methylation of the RASSF1A gene in simian virus 40 infected human mesothelial cells — S. Toyooka, M. Carbone, et al. (2002)
• Simian virus 40 transformation, malignant mesothelioma and brain tumors — F. Qi, M. Carbone, et al. (2011)
• Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity — M. Bocchetta, I. Di Resta, et al. (2000)
• The presence of simian-virus 40 sequences in mesothelioma and mesothelial cells is associated with high levels of vascular endothelial growth factor — P. Cacciotti, L. Strizzi, et al. (2002)

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